GIP Acutely Blunts Insulin- and GLP-1-Induced Muscle Microvascular Perfusion.

UNLABELLED: Glucose-dependent insulinotropic polypeptide (GIP) promotes nutrient storage, but its vascular actions in skeletal muscle remain unclear. To determine whether GIP regulates muscle microvascular perfusion, a key determinant of substrate use, we examined GIP receptor (GIPR) expression in vascular endothelium and assessed GIP effects in vivo in chow-fed and high-fat diet (HFD)-fed rats. Overnight-fasted rats received 120-min infusions of saline or GIP, with or without concurrent insulin or glucagon-like peptide 1 (GLP-1). Immunofluorescence microscopy demonstrated clear GIPR expression in conduit, resistance, and microvascular vessel endothelium. GIP alone did not alter muscle microvascular perfusion in either group but completely abolished insulin- and GLP-1-induced microvascular recruitment. In cultured endothelial cells, GIP dose-dependently increased endothelin-1 (ET-1) secretion and suppressed insulin- or GLP-1-stimulated nitric oxide production. Transcriptomic profiling implicated activation of the GIP-angiotensin II type 1 receptor-ET-1 pathway. In conclusion, GIPR is widely expressed in vascular endothelium. While GIP does not independently recruit muscle microvasculature, it antagonizes insulin- and GLP-1-mediated vasodilation, identifying GIP as a conditional regulator of skeletal muscle perfusion and nutrient delivery, consistent with its physiological effect in directing nutrients toward storage depots.

ARTICLE HIGHLIGHTS: Skeletal muscle microvasculature is essential for nutrient delivery and metabolic regulation, but the vascular actions of glucose-dependent insulinotropic polypeptide (GIP) in muscle are unknown. We investigated whether GIP regulates skeletal muscle microvascular perfusion and interacts with insulin and GLP-1 signaling. GIP receptors are expressed in vascular endothelium, yet GIP alone does not increase muscle perfusion and instead antagonizes insulin- and GLP-1-mediated microvascular recruitment via possibly angiotensin II type 1 receptor-dependent endothelin-1/nitric oxide imbalance. GIP acts as a conditional regulator of skeletal muscle microvascular perfusion, revealing a novel mechanism of tissue-specific incretin regulation of nutrient partitioning.